This invention is in the field of medical procedures, namely laser medical equipment used to perforate or alter tissue for monitoring analyte concentration in bodily fluids.
The traditional method of measuring blood glucose, or other analytes, consists of taking a blood sample and then measuring the analyte concentration in the blood or plasma. The blood is typically collected from a patient utilizing mechanical perforation of the skin with a sharp device such as a metal lancet or needle.
This procedure has many drawbacks, including the possible infection of health care workers and the public by the sharp device used to perforate the skin, as well as the cost of handling and disposal of biologically hazardous waste.
When skin is perforated with a sharp device such as a metal lancet or needle, biological waste is created in the form of the xe2x80x9csharpxe2x80x9d contaminated by the patient""s blood and/or tissue. If the patient is infected with blood-born agents, such as human immunodeficiency virus (HIV), hepatitis virus, or the etiological agent of any other diseases, the contaminated sharp poses a serious threat to others that might come in contact with it. For example, many medical workers have contracted HIV as a result of accidental contact with a contaminated sharp.
Post-use disposal of contaminated sharps imposes both logistical and financial burdens on the end user. These costs are imposed as a result of the social consequences of improper disposal. For example, in the 1980""s improperly disposed biological wastes washed up on public beaches on numerous occasions. Improper disposal also permits others, such as intravenous drug users, to obtain contaminated needles and spread disease.
There exists an additional drawback of the traditional method of using a needle for drawing fluids. The pain associated with being stabbed by a the sharp instrument can be a traumatizing procedure, especially in pediatric patients, causing significant stress and anxiety in the patient. Moreover, the stabbing procedure often must be repeated before sufficient fluid is obtained. For analytes that need to be constantly monitored, patients may not comply with the frequency of measurement due to the pain involved. In the case of diabetics, failure to measure glucose levels can result in a life-threatening situation.
In addition to blood withdrawal, concentrations of analytes in interstitial fluid can be measured for accurate representation of analyte concentration in the blood. Because of the strong barrier properties of the stratum corneum, however, collecting interstitial fluid through the stratum corneum poses problems. To reduce the barrier function of the stratum corneum, a number of different techniques are presently used, these include: (1) using a metal lancet to cut the skin, (2) chemical enhancers, (3) ultrasound, (4) tape stripping, and (5) iontophoresis. Chemical enhancers pose the problem of potentially reacting with the analyte to be measured. Moreover, the time lapse after application to propagation of interstitial fluid is great. Tape stripping is unsatisfactory because of the pain to the patient. Iontophoresis and ultrasound, similarly have drawbacks in the collection time and the quantity of fluid removed. As previously discussed, the use of a metal lancet has the drawback of patient discomfort and the possibility of contamination.
Thus, a need exists for a method to easily measure the constituents in the blood or other bodily fluids, without: (1) the use of a sharp object, (2) the slow speed of fluid collection, or (3) the pain currently associated with the elimination or reduction of the barrier function of the stratum corneum. The method would further obviate the need for disposal of contaminated sharps and eliminate the pain associated with sharp instruments. The desired method would also, ideally, increase patient compliance for monitoring the desired analyte. The method and apparatus disclosed herein achieves these and other goals.
Lasers have been used in recent years as a very efficient precise tool in a variety of surgical procedures. Among potentially new sources of laser radiation, the rare-earth elements are of major interest for medicine. One of most promising of these is a YAG (yttrium, aluminum, garnet) crystal doped with erbium (Er) ions. With the use of this crystal, it is possible to build an erbium-YAG (Er:YAG) laser which can be configured to emit electromagnetic energy at a wavelength (2.94 microns), among other things, which is strongly absorbed by water. When tissue, which consists mostly of water, is irradiated with radiation at or near this wavelength, energy is transferred to the tissue. If the intensity of the radiation is sufficient, rapid heating can result followed by vaporization of tissue can result. In addition, or alternatively, deposition of this energy can result in photomechanical disruption of tissue. Some medical uses of Er:YAG lasers have been described in the health-care disciplines of dentistry, gynecology and ophthalmology. See, e.g., Bogdasarov, B. V., et al., xe2x80x9cThe Effect of Er: YAG Laser Radiation on Solid and Soft Tissuesxe2x80x9d, Preprint 266, Institute of General Physics, Moscow, 1987; Bol""shakov, E. N. et al., xe2x80x9cExperimental Grounds for Er:YAG Laser Application to Dentistryxe2x80x9d, SPIE 1353:160-169, Lasers and Medicine (1989) (these and all other references cited herein are expressly incorporated by reference as if fully set forth in their entirety herein). Laser perforators of the type explained in U.S. Pat. No. 5,643,252, said patent being incorporated by reference herein, have generally been designed to perforate or alter the tissue of a patient to reduce the barrier function of the stratum corneum, thus allowing for transport of fluid through the target tissue.
The present invention employs a laser to perforate or alter the skin of a patient for removal and subsequent analysis of interstitial fluid. These measurements can then be used to approximate analyte concentrations in other bodily fluids, such as blood. Prior to application, the care giver properly selects the wavelength, energy fluence (energy of the pulse divided by the area irradiated), pulse temporal width and irradiation spot size so as to precisely perforate or alter the target tissue to a select depth and eliminate undesired damage to healthy proximal tissue. After perforation or alteration, interstitial fluid is allowed to propagate to the surface of the skin for collection and testing.
According to one embodiment of the present invention, a laser emits a pulsed laser beam, focused to a small spot for the purpose of perforating or altering the target tissue. By adjusting the output of the laser, the laser operator can control the depth, width and length of the perforation or alteration as needed, such as to avoid drawing blood into the interstitial fluid sample.
In another embodiment, continuous-wave or diode lasers may be used to duplicate the effect of a pulsed laser beam. These lasers are modulated by gating their output, or, in the case of a diode laser, by fluctuating the laser excitation current. The overall effect is to achieve brief irradiation, or a series of brief irradiations, that produce the same tissue permeating effect as a pulsed laser.
The term xe2x80x9cperforationxe2x80x9d is used herein to indicate the ablation of the stratum corneum to reduce or eliminate its barrier function. The term xe2x80x9calterationxe2x80x9d of the stratum corneum is used herein to indicate a change in the stratum corneum which reduces or eliminates the barrier function of the stratum corneum and increases permeability without ablating, or by merely partially ablating, the stratum corneum itself. A pulse or pulses of infrared laser radiation at a subablative energy of, e.g., 60 mJ using a TRANSMEDICA(trademark) International, Inc. (xe2x80x9cTRANSMEDICA(trademark)xe2x80x9d) Er:YAG laser (see U.S. Pat. No. 5,643,252, Waner et al., which is incorporated herein by reference) with a beam of radiant energy with a wavelength of 2.94 microns, a 200 xcexcs (microsecond) pulse, and a 2 mm spot size) will alter the stratum corneum. The technique may be used for transdermal drug delivery or for obtaining fluid samples from the body. Different wavelengths of laser radiation and energy levels less than or greater than 60 mJ may also produce the enhanced permeability effects without ablating the skin.
The mechanism for this alteration of the stratum corneum is not certain. It may involve changes in lipid or protein nature or function or be due to desiccation of the skin or mechanical alterations secondary for propagating pressure waves or cavitation bubbles. The pathway that topically applied drugs take through the stratum corneum is generally thought to be through cells and/or around them, as well as through hair follicles. The impermeability of skin to topically applied drugs is dependent on tight cell to cell junctions, as well as the biomolecular makeup of the cell membranes and the intercellular milieu. Any changes to either the molecules that make up the cell membranes or intercellular milieu, or changes to the mechanical structural integrity of the stratum corneum and/or hair follicles can result in reduced barrier function. It is believed that irradiation of the skin with radiant energy produced by the Er:YAG laser causes measurable changes in the thermal properties, as evidenced by changes in the Differential Scanning Calorimeter (DSC spectra as well as the Fourier Transform Infrared (FTIR) spectra of stratum corneum. Changes in DSC and FTIR spectra occur as a consequence of changes in molecules or macromolecular structure, or the environment around these molecules or structures. Without wishing to be bound to any particular theory, we can tentatively attribute these observations to changes in lipids, water and protein molecules in the stratum corneum caused by irradiation of molecules with electromagnetic radiation, both by directly changing molecules as well as by the production of heat and pressure waves which can also change molecules.
Both perforation and alteration change the permeability parameters of the skin in a manner which allows for increased passage of body fluids or pharmaceuticals across the stratum corneum.
The term xe2x80x9clysexe2x80x9d is used herein to indicate the breaking up of the epidermis layer covering a microblister. The energy pulse used to accomplish this is between the energy required for ablation and sub-ablation.
Accordingly, one object of the present invention is to provide a means for perforating or altering the stratum corneum of a patient in a manner that does not result in bleeding. For example, the perforation or alteration created at the target tissue is accomplished by applying a laser beam that penetrates through the stratum corneum layer or both the stratum corneum layer and the epidermis, thereby reducing or eliminating the barrier function of the stratum corneum. This procedure allows for the subsequent removal of fluids, specifically interstitial fluid, through the skin.
Another object of this invention is to draw interstitial fluid through the perforation or alteration site (or allowing the interstitial to propagate on its own to the surface of the skin). The interstitial fluid can then be collected.
In a preferred embodiment, by selection of appropriate wavelength, energy fluence, pulse temporal width and irradiation spot size, the skin tissue is perforated deep into the epidermis. After perforation, interstitial fluid is collected into an awaiting container.
In a further preferred embodiment, by selection of appropriate wavelength, energy fluence, pulse temporal width and irradiation spot size, just the stratum corneum is perforated or altered and the interstitial fluid is then allowed to propagate to surface. The fluid is then collected into a container unit for testing, or the fluid is left on the skin surface for subsequent testing.
In an additional preferred embodiment, before perforation or alteration by the laser device, a blister, preferably a microblister, is created at the surface of the skin by subjecting the skin to sub-atmospheric pressure. This vacuum can be created by a separate device, or the vacuum system can be part of the laser perforator container unit. After the skin has been subjected to sub-atmospheric pressure (a pressure of slightly less than 1 atmosphere), a microblister is formed, whereby the epidermis is separated from the dermis. Interstitial fluid collects in this pocket and the laser perforator is then used to lyse the blister. After lysing, the interstitial fluid that formed inside the blister is collected into a container.
To further the speed in the collection of interstitial fluid, or to increase the delivery of pharmaceuticals into the body, pressure gradients in the tissue can be created. In this embodiment, pressure gradients are created using short rapid pulses of radiant energy on the tissue. This pressure gradient can be used to force substances, such as interstitial fluid, out of the body, or to transfer a substance into the body, through a perforation or alteration site. In another embodiment of this invention, pressure waves, plasma, and cavitation bubbles are created in or above the stratum corneum to increase the permeation of the compounds (e.g., pharmaceuticals) or fluid, gas or other biomolecule removal. This method may simply overcome the barrier function of intact stratum corneum without significant alteration or may be used to increase permeation or collection in ablated or altered stratum corneum. Additionally, to increase diffusion, plasma can be produced by irradiating the surface of the target tissue, or material on the target tissue, with a pulse or pulses of electromagnetic energy from a laser. Prior to treatment, the care giver properly selects the wavelength, energy fluence (energy of the pulse divided by the area irradiated), pulse temporal width and irradiation spot size to create the plasma while limiting undesired damage to healthy proximal tissue. These technique for increasing the diffusion of fluids through the skin is not meant to limit the scope of this invention, but is merely an embodiment. Other techniques can be used, such as manual compression of the skin surrounding the perforation or alteration site, or the care giver can rely simply on the reduced barrier function of the perforation or alteration site for fluid to propagate to the skin surface.
In another embodiment, a typical laser is modified to include a container unit. Such a container unit can be added to: (1) increase the efficiency in the collection of fluids; (2) further testing of the collected sample, (3) apply a vacuum to the skin surface, (4) reduce the noise created when the laser beam perforates the patient""s tissue; and (5) collect the ablated tissue. The optional container unit is alternatively evacuated to expedite the collection of the released materials, such as the fluids, or to expedite the blistering of the tissue. The container can also be used to collect only ablated tissue. The noise created from the laser beam""s interaction with the patient""s skin may cause the patient anxiety. The optional container unit reduces the noise intensity and therefore alleviates the patient""s anxiety and stress. The container unit also minimizes the risk of cross-contamination and guarantees the sterility of the collected sample. The placement of the container unit in the use of this invention is unique in that it covers the tissue being irradiated, at the time of irradiation by the laser beam, and is therefore able to collect the fluid and/or ablated tissue as the perforation or alteration occurs.
An additional object of this invention is to allow the taking of measurements of various fluids constituents, such as glucose, collected through the perforation or alteration site. Typical testing techniques include infrared spectrometry, enzymatic analysis, electrochemical analysis and other means. The testing can be incorporated into the laser perforator device or the testing can be completed on the fluid after the container unit has been removed from the device. Additionally, testing can be completed on the surface of the skin, at the perforation or ablation site, after the interstitial fluid has propagated through the target tissue.
An additional object of this invention is to administer pharmaceuticals after measurement of the interstitial fluid. The appropriate drug dose can be delivered manually or automatically. Drug delivery can be triggered in combination with the monitoring of the desired analyte. For example, glucose measurements can be used to trigger the administration of insulin in diabetics.
A further object of this invention is to allow drugs to be administered continually on an outpatient basis over long periods of time. The speed and/or efficiency of drug delivery is thereby enhanced for drugs which were either slow or unable to penetrate skin.
A further object of this invention is to avoid the use of sharps. The absence of a contaminated sharp will eliminate the risk of accidental injury and its attendant risks to health care workers, patients, and others that may come into contact with the sharp. The absence of a sharp in turn obviates the need for disposal of biologically hazardous waste. Thus, the present invention provides an ecologically sound method for removing bodily fluids or administering pharmaceuticals.
A typical laser used for this invention requires no special skills to use (for example, the TRANSMEDICA(trademark) Er:YAG laser). It can be small, lightweight and can be used with regular or rechargeable batteries. The greater the laser""s portability and ease of use, the greater the utility of this invention in a variety of settings, such as a hospital room, clinic, or home.
Safety features can be incorporated into the laser that require that no special safety eyewear be worn by the operator of the laser, the patient, or anyone else in the vicinity of the laser when it is being used.